Transcript Current and Emerging Infectious Diseases

Current and Emerging
Infectious Diseases
http://www.cdc.gov/ncidod/diseases/eid/disease_sites.htm
 Infectious Disease Information: Emerging
Infectious DiseasesInformation by
Emerging or Reemerging Infectious
Disease Topic
– drug-resistant infections (antimicrobial resistance)
– bovine spongiform encephalopathy (Mad cow
disease) and variant Creutzfeldt-Jakob disease
(vCJD)
– campylobacteriosis
– Chagas disease
– cholera
– cryptococcosis
– cryptosporidiosis (Crypto)
– cyclosporiasis
– cysticercosis
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dengue fever
diphtheria
Ebola hemorrhagic fever
Escherichia coli infection
group B streptococcal infection
hantavirus pulmonary syndrome
hepatitis C
hendra virus infection
histoplasmosis
HIV/AIDS
influenza
Lassa fever
legionnaires' disease (legionellosis) and Pontiac fever
Leptospirosis
listeriosis
Lyme disease
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malaria
Marburg hemorrhagic fever
measles
meningitis
monkeypox
MRSA (Methicillin Resistant Staphylococcus aureus)
Nipah virus infection
norovirus (formerly Norwalk virus) infection
pertussis
plague
polio (poliomyelitis)
rabies
Rift Valley fever
rotavirus infection
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salmonellosis
SARS (Severe acute respiratory syndrome)
shigellosis
smallpox
sleeping Sickness (Trypanosomiasis)
tuberculosis
tularemia
valley fever (coccidioidomycosis)
VISA/VRSA - Vancomycin-Intermediate/Resistant
Staphylococcus aureus
– West Nile virus infection
– yellow fever
Emerging Infectious Diseases:
A 10-Year Perspective
 HIV/AIDS
 Malaria
 Tuberculosis
 Influenza
 West Nile Virus
 SARS
 Potential Bioterror Agents
Current and Emerging
Infectious Diseases
 Infectious diseases have been an ever-
present threat to mankind.
 From the biblical plagues and the Plague of
Athens in ancient times, to the Black Death of
the Middle Ages, the 1918 "Spanish Flu"
pandemic, and more recently, the HIV/AIDS
pandemic, infectious diseases have
continued to emerge and reemerge in a
manner that defies accurate predictions.
Current and Emerging
Infectious Diseases
 The past 10 years (1994–2004) have been no
exception, as many new and reemerging
microbial threats have continued to challenge
the public health and infectious disease
research communities worldwide.
 Since 1994, when Emerging Infectious
Diseases made its publication debut,
significant strides in the global fight against
the HIV/AIDS pandemic have been made.
Current and Emerging
Infectious Diseases
 The infectious disease community has
confronted several other newly
emerging pathogens,
– Severe acute respiratory syndrome–
associated coronavirus (SARS-CoV),
– Henipaviruses (Hendra and Nipah), and,
– Avian influenza viruses that have caused
illness and deaths in humans with the
threat of evolution into a pandemic.
Current and Emerging
Infectious Diseases
 In addition, historically established infectious
diseases, such as West Nile fever, human
monkeypox, dengue, tuberculosis, and
malaria have reemerged or resurged,
sometimes in populations that previously had
been relatively exempt from such affronts.
 Over the past decade, strains of common
microbes such as Staphylococcus aureus
and Mycobacterium tuberculosis have
continued to develop resistance to the drugs
that once were effective against them.
Current and Emerging
Infectious Diseases
 Such antimicrobial-resistant
microorganisms, which defy
conventional therapies and pose a
threat to public health, underscore the
need for a robust pipeline of new
antimicrobial agents based on
innovative therapeutic strategies, new
vaccines, and other preventive
measures.
Current and Emerging
Infectious Diseases
 Perhaps most disturbing, the United
States has recently experienced a
deliberately spread infectious disease in
the form of 22 anthrax infections,
including 5 anthrax-related deaths
resulting from bioterrorism in 2001.
These cases were accompanied by
widespread psychological sequelae and
societal and economic disruptions.
Current and Emerging
Infectious Diseases
 These emerging and reemerging
infectious diseases are superimposed
on a substantial baseline of established
infectious diseases.
 Although annual deaths and lost years
of healthy life from infectious diseases
have decreased over the past decade,
the worldwide impact from infectious
diseases remains substantial.
Current and Emerging
Infectious Diseases
 Overall, infectious diseases remain the third
leading cause of death in the United States
each year and the second leading cause of
death worldwide .
 Of the estimated 57 million deaths that occur
throughout the world each year, ≈15 million,
>25%, are directly caused by infectious
diseases.
 Millions more deaths are due to secondary
effects of infections .
 Figure 1. Leading causes of death worldwide
(estimates for 2002). Nearly 15 million (>25%) of
the 57 million annual deaths worldwide are caused
by infectious disease.
Current and Emerging
Infectious Diseases
 Infectious diseases also lead to
compromised health and disability,
accounting for nearly 30% of all
disability-adjusted life years (DALYs)
worldwide (1 disability-adjusted life year
is 1 lost year of healthy life). Infectious
diseases that contribute to the nearly
1.5 billion total DALYs each year are
categorized in Figure 2.
 Figure 2. Leading causes of disability-adjusted
life years (DALYs) due to infectious and parasitic
diseases (2002 estimates)...
Current and Emerging
Infectious Diseases
 In the United States, the Centers for
Disease Control and Prevention has
devised strategies to prevent, monitor,
and contain disease outbreaks.
 Within the National Institutes of Health,
the National Institute of Allergy and
Infectious Diseases (NIAID) is the lead
agency for infectious disease research.
Current and Emerging
Infectious Diseases
 Over the past decade, the NIAID budget
has quadrupled; spending on emerging
infectious diseases has increased from
<$50 million in 1994 to >$1.7 billion
projected for 2005, a boost due in large
part to increases in funding for
biodefense research.
 Figure 3. The overall NIAID budget rose from $1.06 billion
in FY1994 to $4.4 billion (estimated) in FY2005. Funding
for emerging infectious diseases rose from $47.2 million in
FY1994 to $1.74 billion in FY2005 (est.).
Current and Emerging
Infectious Diseases
 NIAID-supported intramural and
extramural investigators have
contributed substantially to the global
effort to identify and characterize
infectious agents, decipher the
underlying pathways by which they
cause disease, and develop preventive
measures and treatments for many of
the world's most dangerous pathogens.
Current and Emerging
Infectious Diseases
 This review briefly highlights some of
the research strides made by NIAIDsupported investigators during the past
decade in preventing and combating
emerging and reemerging infectious
diseases threats.
HIV/AIDS
 HIV/AIDS has resulted in the death of >20
million persons throughout the world and is
the leading cause of death among persons
15–59 years of age.
 Approximately 40 million persons are
estimated to be living with HIV infection.
 In the United States, an estimated 1 million
persons are infected with HIV, and 40,000
new infections occur each year.
HIV/AIDS
 Since its recognition in 1981, the
disease has killed more than half a
million people in the United States.
 Despite these grim statistics, reason for
hope exists.
 Basic research has yielded major
insights into the pathogenic
mechanisms of HIV disease.
HIV/AIDS
 This knowledge paved the way for the
development of >20 antiretroviral
medications approved by the Food and
Drug Administration (FDA) that target
HIV, as well as novel strategies for
prevention and vaccine development.
HIV/AIDS
 With the use of combinations of drugs
that target different proteins involved in
HIV pathogenesis (a treatment strategy
known as highly active antiretroviral
therapy [HAART]), rates of death and
illness in the United States and other
industrialized countries have been
dramatically reduced (Figure 4).
 Figure 4. AIDS cases, AIDS deaths, and persons
living with AIDS in the United States, 1981–2003
HIV/AIDS
 Although the death rate due to HIV/AIDS in
Europe and North America has fallen by 80%
since HAART was introduced, relatively few
people in poor countries have reaped these
benefits. New initiatives such as the Global
Fund to Fight AIDS, Tuberculosis, and
Malaria and the President's Emergency Plan
for AIDS Relief promise to greatly reduce the
disparity between rich and poor countries with
regard to access to HIV treatment, care, and
prevention services.
HIV/AIDS
 The greatest challenge in HIV/AIDS research
remains developing a vaccine that can either
prevent the transmission of the virus or,
failing that, halt progression to AIDS.
 Since 1987, NIAID has funded >70 clinical
trials evaluating >50 different HIV vaccine
candidates.
 Unfortunately, the first large-scale phase 3
trial of an HIV vaccine reported in 2003 had
disappointing results .
HIV/AIDS
 Many different vaccine strategies, including viral
and bacterial vectors, DNA vaccines, viruslike
particle vaccines, and peptide vaccines are being
investigated, and ≈15 clinical trials in humans are
under way.
 The effects of various adjuvants and different routes
of administration also are being tested.
 HIV vaccine developers face formidable scientific
obstacles, including the virus's genetic diversity and
the lack of a clear understanding of the correlates of
protective immunity in HIV infection.
HIV/AIDS
 A critical and so far elusive milestone is the
discovery of a stable and immunogenic
conformational epitope of the HIV envelope
that would elicit broadly reactive
neutralizing antibodies against primary
isolates of HIV.
HIV/AIDS
 To overcome these challenges,
collaborations involving government,
academia, industry, and philanthropies and
new cross-sector partnerships such as the
Global HIV Vaccine Enterprise, a virtual
consortium of independent organizations,
are being established to advance HIV
vaccine research and foster greater
collaboration among HIV vaccine
researchers worldwide .
Malaria
 The social, economic, and human toll
exacted by malaria globally is widespread
and profound. Each year, acute malaria
occurs in >300 million people and results in
>1 million deaths worldwide. Most of these
deaths occur in young children who live in
sub-Saharan Africa.
Malaria
 In humans, the disease is caused by one of 4
species of Plasmodium, a single-cell
parasite transmitted by anopheline
mosquitoes.
 In 2002, the complete genomic sequence of
Plasmodium falciparum as well as that of
the mosquito vector Anopheles gambiae
were completed as the result of a
multinational effort.
Malaria
 With the genomic sequences of the parasite
and its human and mosquito hosts now
available, researchers have powerful tools
to further characterize the genes and
proteins involved in the life cycle of the
parasite, and they are using this information
to design effective drugs and vaccines.
Malaria
 Drug-resistant Plasmodium strains are widespread,
as are insecticide-resistant strains of the
mosquitoes that carry the parasites.
 Mutations in both parasites and mosquitoes that
confer drug and insecticide resistance have been
identified.
 For example, genetic analysis and molecular
epidemiology studies of P. falciparum have shown
that resistance to chloroquine and other
antimalarials is caused by a mutation in a single
gene, called pfcrt .
Malaria
 This information is being used to track the
spread of drug-resistant strains of the
parasite and identify new drug targets.
Researchers also are exploiting the new
genomic information to create genetically
altered mosquitoes that resist parasite
infection and to develop new compounds
that overcome or avoid resistance to
existing pesticides.
Malaria
 Developing an effective antimalarial
vaccine has been a challenge; however, an
international research team recently
developed a vaccine that shows promise in
preventing malaria among children in
Mozambique.
 The vaccine prevented infection and severe
disease in a substantial percentage of
children tested, a breakthrough with the
potential of saving millions of lives .
Tuberculosis
 Another ancient microbial scourge that has
reemerged in recent years is tuberculosis
(TB), caused by infection with the
bacterium Mycobacterium tuberculosis.
 This infection is estimated to be prevalent in
one third of the world's population.
 From this reservoir, 8 million new cases of
TB develop worldwide each year that carry
a death toll of >2 million.
Tuberculosis
 TB is especially prevalent among persons infected
with HIV.
 The only currently available TB vaccine, M. bovis
bacillus Calmette-Guérin (BCG), offers some
protection, but its effect diminishes with time.
 TB drug treatment is effective, but adherence to
lengthy therapeutic regimens is difficult to
maintain, and multidrug-resistant TB is on the rise
in many countries.
Tuberculosis
 Researchers are applying state-of-the-art genomic
and postgenomic techniques to identify key
molecular pathways that could be exploited to
develop improved TB interventions and vaccines
 In 2004, for the first time in 60 years, 2 new
vaccines designed to prevent TB entered phase 1
clinical trials in the United States .
 Many promising new anti-TB drug candidates also
are now entering the drug pipeline.
Tuberculosis
 Derivatives of known anti-TB drugs, such
as thiolactomycin and ethambutol, are
currently being screened for activity against
M. tuberculosis.
 Preclinical development of a highly
promising candidate, SQ109 is nearing
completion.
Influenza
 Each year, influenza develops in up to 20%
of all Americans, and >200,000 are
hospitalized with the disease. Although
influenza is commonplace and generally
self-limited, an estimated 36,000 Americans
die each year from complications of the
disease. Worldwide, severe influenza
infections develop in 3–5 million people
annually, and 250,000–500,000 deaths
occur.
Influenza
 Outbreaks of avian influenza recently have drawn
attention worldwide, particularly in Southeast
Asia, where at least 55 persons have been infected
and 42 have died since January 2004.
 The current strain of H5N1 avian influenza is
highly pathogenic; it has killed millions of
chickens and other birds.
 Although the virus can cross species to infect
humans, few suspected cases of human-to-human
transmission have been reported .
Influenza
 However, the virus could acquire
characteristics that allow it to be readily
transmitted among humans, which could
cause a worldwide influenza pandemic,
with the potential for killing millions of
people.
 In 1918, a pandemic of the "Spanish Flu"
killed 20–50 million people worldwide.
Influenza
 Recently, the NIH Influenza Genomics Project
was initiated; it will conduct rapid sequencing of
the complete genomes of the several thousand
known avian and human influenza viruses as well
as those that emerge in the future.
 Approximately 60 genomes are expected to be
sequenced each month.
 This project should also illuminate the molecular
basis of how new strains of influenza virus emerge
and provide information on characteristics that
contribute to increased virulence.
Influenza
 Many researchers believe that the H5N1 virus
shows the greatest potential for evolving into the
next human pandemic strain. Avian H9N2 viruses
also have infected humans and have the potential
to cause a pandemic.
 To prepare for this possibility, the development of
vaccines to prevent infection with H5N1 and
H9N2 viral strains is being supported.
Influenza
 Researchers also are working to develop a live-
attenuated vaccine candidate directed against each
of the 15 hemagglutinin proteins that have been
isolated, an effort that may speed the development
of a vaccine against a potential pandemic strain.
 Using reverse genetics, researchers developed a
genetically engineered vaccine candidate (called a
reference virus) against H5N1 in a matter of
weeks, demonstrating the power of this
technology.
Influenza
 The new H5N1 candidate was tested in animals to
confirm that it was no longer highly pathogenic,
and vaccine manufacturers are using the reference
virus to develop inactivated vaccines that will be
evaluated in phase 1 and 2 clinical trials.
 Reverse genetics also has been used to identify a
specific genetic mutation in a H5N1 viral gene,
called PB2, which makes the virus especially
lethal.
Influenza
 This discovery may be useful in designing
antiviral drugs and vaccine candidates.
 Experiments also are being conducted in which
genes isolated from the 1918 influenza strain are
cloned into avirulent influenza strains.
 Researchers recently showed that the
hemagglutinin gene from the 1918 virus conferred
a high degree of pathogenicity to avirulent
influenza strains when introduced into mice.
Influenza
 These recombinant viruses and others are being
evaluated in various animal models, including
nonhuman primates, to further determine how
genes of the 1918 virus contributed to its ability to
spread so rapidly and cause so many deaths, and to
understand the molecular basis for its
unprecedented virulence.
 Previous research established the foundation for
developing a live-attenuated nasal flu vaccine that
was approved by FDA in 2003 for use in healthy
adults and children 5–49 years of age.
West Nile Virus
 West Nile virus (WNV), long endemic in Africa,
West Asia, Europe, and the Middle East,
represents a reemerging disease that only recently
arrived in the United States.
 The virus first appeared in the New York City area
in 1999, where WNV-related disease was reported
in 62 persons.
 It has continued to spread throughout the United
States in subsequent summers, infecting ever
larger populations, particularly in 2003.
West Nile Virus
 Research has led to several promising vaccine
candidates against WNV.
 One of these, based on a licensed yellow fever
vaccine virus that contains 2 WNV genes, has
been tested in nonhuman primates; it is currently
being evaluated in human clinical trials.
 A second vaccine developed at NIH uses an
attenuated dengue virus into which WNV genes
have been inserted.
West Nile Virus
 This vaccine protects monkeys and horses
against WNV infection, and a clinical trial
is now underway.
 Subunit and DNA vaccines against WNV
are also in various stages of development
and testing.
 Several innovative therapies also are being
tested to treat persons already infected with
WNV.
West Nile Virus
 In a clinical trial at >60 sites across the United
States and Canada, the protective effect of an
immunoglobulin product is being tested in
hospitalized patients who are at high risk for or
who have WNV encephalitis.
 Technology also has been developed to screen
large numbers of chemical compounds for
antiviral activity.
 As of February 2005, 1,500 compounds had been
screened in vitro, and 2% were shown to have
antiviral activity against WNV.
West Nile Virus
 These compounds are undergoing further evaluation in
hamster and mouse models of disease.
 Partnerships with small biotechnology companies
have been formed to develop more sensitive and rapid
tests for detecting WNV infections.
 Other studies are ongoing to evaluate the roles of
various mosquito vectors and animal reservoirs in
virus transmission, to test novel mosquito control
methods, and to limit the impact of insecticide
resistance on mosquito control.
SARS
 The emergence of SARS in Asia in late 2002, and
the speed with which it was characterized and
contained, underscores the importance of
cooperation between researchers and public health
officials .
 NIAID is focusing its resources on developing
diagnostics, vaccines, and novel antiviral
compounds to combat SARS-CoV.
 Basic research on the pathogenesis of the disease
to identify appropriate targets for therapeutics and
vaccines, as well as clinical studies to test new
therapies, is also being supported.
SARS
 Among many projects that have received support
are the development of a "SARS chip," a DNA
microarray to rapidly identify SARS sequence
variants, and a SARS diagnostic test based on
polymerase chain reaction technology.
 Researchers have developed 2 candidate vaccines,
based on the SARS-CoV spike protein, that
protect mice against SARS.
 Another promising vaccine protects against
infection in monkeys when delivered intranasally.
SARS
 Passive immunization as a treatment for SARS
patients is also being investigated.
 Both mouse and human antibodies against SARS
can prevent infection when introduced into
uninfected mice, and an international collaboration
has developed a rapid method of producing human
anti-SARS antibodies.
 In 2004, in vitro screening of >20,000 chemicals
identified ≈1,500 compounds with activity against
SARS-CoV, at least 1 of which has been selected
by industry as a candidate for further clinical
development.
Potential Bioterror Agents
 The September 11, 2001, attacks on the
World Trade Center and Pentagon, and the
subsequent anthrax attacks that infected 22
people and killed 5, propelled the U.S.
government to expand its biodefense
research program.
Potential Bioterror Agents
 These studies are based on 3 approaches:
– basic research aimed at understanding structure,
biology, and mechanisms by which potential
bioweapons cause disease;
– studies to elucidate how the human immune
system responds to these dangerous pathogens;
– development of the technology to translate
these basic studies into safe and effective
countermeasures to detect, prevent, and treat
diseases caused by such pathogens .
Potential Bioterror Agents
 At least 60 major NIAID initiatives involving
intramural and extramural scientists and industrial
partners were funded in fiscal years 2002–2004.
 Among them are funding for 8 Regional Centers
of Excellence for Biodefense and Emerging
Infectious Diseases Research and construction of 2
National Biocontainment Laboratories and 9
Regional Biocontainment Laboratories.
 These facilities will provide the secure space
needed to carry out the nation's expanded
biodefense research program.
Potential Bioterror Agents
 The genomes of all biological agents considered to
pose the most severe threats have been sequenced
by researchers.
 In addition, programs have been expanded and
contracts awarded to screen new chemical
compounds as possible treatments for bioterror
attacks.
 New animal models have been developed to test
promising drugs, and repositories have been
established to catalog reagents and specimens.
Potential Bioterror Agents
 In addition, research to understand the body's
protective mechanisms against pathogens is being
pursued.
 The Cooperative Centers for Translational
Research on Human Immunology and Biodefense
will focus on studies of the human immune
response to potential agents of bioterror, while
other programs are focused on the innate immune
system and the development of ways to boost
innate immunity.
Potential Bioterror Agents
 NIAID also has been very active in vaccine
development as a biodefense countermeasure .
 The Institute has supported the development of a
next-generation anthrax vaccine, known as
recombinant protective antigen (rPA); it is
undergoing clinical trials, and contracts for the
Strategic National Stockpile to acquire it have
recently been awarded.
Potential Bioterror Agents
 Several new smallpox vaccines also are
being tested for safety and efficacy.
 Preliminary studies in mice and monkeys
show that one of these, modified vaaccinia
Ankara (MVA), protects against poxvirus
infections.
 Clinical trials of the MVA vaccine are
ongoing at NIAID Vaccine Research Center
and elsewhere.
Potential Bioterror Agents
 A clinical trial of a novel DNA vaccine
against Ebola virus also is under way;
human testing of an adenovirus-vectored
Ebola vaccine is planned for 2005.
 Vaccine manufacturing and clinical trials
also are planned for a new, recombinant
vaccine against plague that is highly
effective in mice and nonhuman primates.
Challenges for the Future
 Scientists—government and academic, together
with their industrial partners and international
collaborators—have made great strides over the
past 10 years in understanding many of the
pathogenic mechanisms of emerging and
reemerging infectious diseases.
 Many of these discoveries have been translated
into novel diagnostics, antiviral and antimicrobial
compounds, and vaccines, often with
extraordinary speed.
Challenges for the Future
 However many challenges remain.
 Paramount among these is developing a safe and
effective HIV vaccine.
 The evolution of pathogens with resistance to
antibacterial and antiviral agents continues to
challenge us to better understand the mechanisms
of drug resistance and to devise new ways to
circumvent the problem.
 These efforts will pave the way for developing
countermeasures against deliberately engineered
microbes.
Challenges for the Future
 If history is our guide, we can assume that the
battle between the intellect and will of the human
species and the extraordinary adaptability of
microbes will be never-ending.
 To successfully fight our microbial foes, we must
continue to vigorously pursue research on the
basic mechanisms that underlie microbial
pathogenesis and develop novel strategies to
outwit theses ingenious opponents.
 The past 10 years have been challenging but no
more so than will be the future.